Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disease with yet unknown etiology. IPF leads to death in 3.5-4 years from initial diagnosis in more than 50% of the patients, irrespective of treatment (Travis, et al., 2013, Am. J. Resp. Crit. Care Med. 188:733-748). Despite extensive research efforts, its pathogenesis is still elusive and controversial (Selman, et al., 2001, Ann. Int. Med. 134:136-151; Selman, et al., 2008, PLoS Med. 5:e62). See also www dot ncbi dot nlm dot nih dot gov/pubmed/24875841; www dot nejm dot org/doi/full/10 dot 1056/NEJMoa1402584; www dot nejm dot org/doi/full/10 dot 1056/NEJMoa1402582.
With a gradually increasing worldwide incidence and no proven therapies other than lung transplantations, IPF treatment represents a major challenge for both pharmaceutical industries and chest physicians. To date, all available treatment agents have been delivered systemically, either orally or subcutaneously. In addition to their limited therapeutic efficacy, use of the majority of these agents has been associated with side effects, ranging from major side effects (such as immune suppression and subsequent infections, acute exacerbations of disease and excessive bleeding) to minor side effects (including gastrointestinal complications, such as diarrhea and nausea) that significantly affect patient quality of life. So far, none of the agents tried, had any significant effect on patient survival.
Early during embryonic development, definitive embryonic progenitor cells of the developing foregut become committed to various organ domains including the lung and thyroid. In line with the premise of common embryonic origin, lung and thyroid share several common transcriptional regulators of their development such as Nkx2-1 and thyroid transcription factor (TTF)-1. In particular, Nkx2-1 knockout mice display lung and thyroid agenesis, while humans born with Nkx2-1 gene mutations develop pediatric lung disease, hypothyroidism and neurological impairment. In addition, TTF-1, a 38KD nuclear transcription factor that belongs in the Nkx2 superfamily and is predominantly found in both normal type II alveolar epithelial cells and thyroid tissue, plays an essential role in epithelial morphogenesis, stimulating the synthesis of surfactant proteins and regulating secretory product gene transcription in Clara cells. TTF-1 is used by pathologists as a reliable histologic marker in the differential diagnosis of both thyroid tumors as well as pulmonary adenocarcinoma. Studies in murine models have shown that exogenous administration of thyroid hormones (T4-thyroxine and its potent derivative-triiodothyronine-T3) accelerate surfactant production, alveolar formation and fetal lung maturation. Unfortunately, investigational trials of thyroid replacement therapy for premature infants with respiratory distress syndrome (RDS) showed mixed irreproducible results. The exact mechanisms through which thyroid hormones exert their therapeutic potentials are unknown, and these compounds have not been successfully used in the treatment of lung fibrosis.
There is a need in the art to identify novel therapeutic treatments that can be used to treat or prevent fibrotic lung diseases, such as idiopathic pulmonary fibrosis. The present invention addresses and meets this need.